Background: The envelope glycoprotein of the human (HIV) and related simian (SIV) immunodeficiency virus are synthesized as gp160 precursors which are processed into two non-covalently associated glycoproteins: gp120 and gp41. The gp120 mediates viral entry into the host cell by binding to the cellular receptor CD4 and a chemokine coreceptor, both of which are located on the host cell surface. This binding induces conformational changes in the transmembrane gp41, which facilitates membrane fusion between the viral and host membranes. An understanding of these processes at the molecular level may lead to a direct means of inhibiting HIV infection. As HIV pg41, and the closely related SIV gp41, are heavily glycosylated transmembrane proteins determination of their high resolution structures is a very difficult problem. Results: In an incremental approach, we have studied the structure of (non-glycosylated) functional domains of gp41. The most important region of gp41 is the ectodomain region, located on the outer surface of the viral membrane, which directly mediates membrane fusion events. Both HIV and SIV gp41 ectodomains have been expressed in E.coli. For the SIV gp41, both the NMR and X-ray structures have been solved. The structure determined by both methods is a rod-like trimer comprising three parallel N-terminal alpha-helices assembled as a coiled-coil in the center with three antiparallel C-terminal alpha-helices packed on the outside with highly flexible loops connecting the inner and outer helices. Results: To gain further insight into gp41 function we have expressed regions of the protein for which there is currently no structural information, namely, the extremely hydrophobic N-terminal fusion peptide and those regions of the protein predicted to be associated with lipid. We have designed novel fusion proteins for the expression of these proteins in bacteria. The proteins produced are being studied by new NMR techniques (A. Bax) designed for the structural analysis of membrane proteins and peptides. In other studies we are producing regions of the HIV gp41 ectodomain in order to raise antibodies against potential receptor-activated conformations. Significance and future direction: More detailed structure determinations of the whole gp41 protein will allow a more rational approach to the design of novel peptide inhibitors.